Intrahepatic Cholangiocarcinoma (ICC) is a relatively rare form of liver cancer. However, in the past decades the incidence of ICC has been increasing in the US. ICC is a deadly disease with few treatment options. ICC clearly represents a type of cancer with unmet medical need as there is very limited NIH funded research on ICC and there is no FDA approved targeted therapy for ICC. Aberrant lipid metabolism has long been recognized as a major metabolic event during cancer development. However, virtually all the studies have been focused solely on the increased de novo lipogenesis as the source for fatty acids required for tumor cell growth. The role of exogenous fatty acids has been largely ignored. Recently, we discovered that de novo fatty acid synthesis pathway genes are downregulated in human ICC samples, and de novo lipogenesis is not required for activated AKT and Notch oncogenes (AKT/NICD) induced ICC development in mice. The results suggest that ICCs may depend on fatty acid uptake for the lipid formation during cell growth. Indeed our preliminary studies showed that human and mouse ICC cells express fatty acid uptake transporters, including FATP1, FATP2 and FATP5; and human ICC cells fail to grow in lipoprotein deficient medium. Based on these observations, we hypothesize that FATP1, FATP2 and FATP5 are required for human ICC cell growth and AKT/NICD induced ICC pathogenesis in mice. The hypothesis will be bested in 2 aims. In aim 1, we will determine the FATPs which are required for ICC cell growth in vitro. And in aim 2, we will determine the FATPs which are required for AKT/NICD induced ICC formation in mice. This application represents the synergistic effects by Dr. Xin Chen of UCSF, an expert in liver cancer research; and Dr. Andreas Stahl of UC Berkeley, an expert in Fatty acid transporters and liver diseases. The study will uncover a previously ignored area of fatty acid metabolism in tumor development. The study will shed light into how fatty acid uptake and possibly obesity contributes to tumorigenesis; therefore provide novel mechanistic insight into the molecular events leading to tumor initiation and progression. The results will also likely provide novel strategy for ICC prevention and treatment.